DESCRIPTION(Applicant's abstract reproduced verbatim): Tight regulation of the focal adhesion kinase (FAK) tyrosine kinase activity is likely essential for normal growth and motility of developing neurons. FAK has 3 alternatively spliced isoforms that specifically regulate kinase activity in the brain, suggesting the importance of exquisite regulation of FAK in the nervous system. Cell culture studies have demonstrated that FAK can mediate integrin-stimulated cell migration and attachment to the cytoskeleton, activate the MAP kinase pathway, trigger anchorage-dependent survival signals, and respond to a variety of growth factors. Given these abundant and biologically significant functions, an essential challenge is to clarify the role of specific FAK signaling pathways in an in vivo, physiological context. Germline FAK deficiency results in early lethality (E8.5) precludes later developmental study. Therefore, in this fellowship I will: Aim 1) generate a "knock-in" point mutation in the ATP binding site of FAK which will result in a kinase dead (KD) FAK protein. The hypothesis is that a kinase-dead FAK mouse phenotype will be less severe than a complete null and reveal those physiological processes which are reliant on kinase signaling pathways and those which are kinase-independent. Aim 2) Characterize the in vivo consequences of kinase-dead (KD) FAK in axonal tract formation and cell survival. Assay growth cone navigation errors at the mouse optic chiasm and evaluate neuronal cell survival in the neural crest and the dorsal root ganglia (DRG). Aim 3) Evaluate the role of KD-FAK in regulation of integrin-mediated contacts, phosphorylation of proteins associated with the neuronal cytoskeleton, response to growth factor stimulation, and in the induction of anchorage-independent cell survival.